Zhou H, Suzuki M, Randers-Pehrson G, Vannais D, Chen G, Trosko J E, Waldren C A, Hei T K
Center for Radiological Research, College of Physicians and Surgeons, and Environmental Health Sciences, School of Public Health, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14410-5. doi: 10.1073/pnas.251524798.
Based principally on the cancer incidence found in survivors of the atomic bombs dropped in Hiroshima and Nagasaki, the International Commission on Radiation Protection (ICRP) and the United States National Council on Radiation Protection and Measurements (NCRP) have recommended that estimates of cancer risk for low dose exposure be extrapolated from higher doses by using a linear, no-threshold model. This recommendation is based on the dogma that the DNA of the nucleus is the main target for radiation-induced genotoxicity and, as fewer cells are directly damaged, the deleterious effects of radiation proportionally decline. In this paper, we used a precision microbeam to target an exact fraction (either 100% or < or =20%) of the cells in a confluent population and irradiated their nuclei with exactly one alpha particle each. We found that the frequencies of induced mutations and chromosomal changes in populations where some known fractions of nuclei were hit are consistent with non-hit cells contributing significantly to the response. In fact, irradiation of 10% of a confluent mammalian cell population with a single alpha particle per cell results in a mutant yield similar to that observed when all of the cells in the population are irradiated. This effect was significantly eliminated in cells pretreated with a 1 mM dose of octanol, which inhibits gap junction-mediated intercellular communication, or in cells carrying a dominant negative connexin 43 vector. The data imply that the relevant target for radiation mutagenesis is larger than an individual cell and suggest a need to reconsider the validity of the linear extrapolation in making risk estimates for low dose, high linear-energy-transfer (LET) radiation exposure.
主要基于广岛和长崎原子弹爆炸幸存者的癌症发病率，国际辐射防护委员会（ICRP）和美国国家辐射防护与测量委员会（NCRP）建议，低剂量暴露的癌症风险估计应通过线性无阈值模型从高剂量外推得出。这一建议基于这样一种教条，即细胞核中的DNA是辐射诱导遗传毒性的主要靶点，并且由于直接受损的细胞较少，辐射的有害影响会成比例下降。在本文中，我们使用精确微束靶向汇合群体中精确比例（100%或≤20%）的细胞，并对每个细胞核精确照射一个α粒子。我们发现，在已知部分细胞核受到照射的群体中，诱导突变和染色体变化的频率与未受照射细胞对反应有显著贡献是一致的。事实上，用单个α粒子照射汇合的哺乳动物细胞群体的10%，所产生的突变率与照射群体中所有细胞时观察到的相似。在用1 mM剂量的辛醇预处理的细胞中，这种效应被显著消除，辛醇会抑制间隙连接介导的细胞间通讯，或者在携带显性负性连接蛋白43载体的细胞中也是如此。这些数据表明，辐射诱变的相关靶点大于单个细胞，并表明有必要重新考虑在进行低剂量、高线性能量传递（LET）辐射暴露的风险估计时线性外推法的有效性。
